With the advance of aging of society, the increase of patients suffering from dementia has been causing a social problem, and about 90% thereof is occupied with Alzheimer-type dementia and cerebrovascular dementia. With respect to the symptom of dementia, short- and long-term dysmnesia is a fundamental and common core symptom, therefore it is considered that the dementia is composed of dysmnesia, disorientation due to dysmnesia and higher brain dysfunction associated therewith. In the patients suffering from dementia, the functions of various neurotransmitter systems are remarkably decreased mainly in the cerebral cortex and the limbic system, additionally the function of cerebral energy metabolism is also decreased. Especially in the patients with Alzheimer-type dementia, the hypofunctions of neurotransmission are found in cholinergic, glutamatergic, neuropeptidergic and monoaminergic system, and it is suggested that the main cause of Alzheimer-type dementia is dysfunction of such neurotransmitter systems [Coyle, J. T. et al., Science, 219, 1184-1190 (1983); Gottfries, C. G. et al., Psychopharmacology, 86, 245-252 (1985)]. Besides, from the viewpoint of the neurotoxicity induced by β-amyloid peptide, it is guessed that the loss of hippocampal neurons through the accumulation of β-amyloid peptide in senile plaque on the surface of the cell is involved in the mechanism of disease onset, and is also one of the main causes of Alzheimer-type dementia [Selkoe D. J., Annu. Rev. Neurosci., 12, 463-490 (1989)].
On the basis of the finding that the remarkable neuronal dysfunction associated with cholinergic system is a cause of dysmnesia in dementia as suggested above, the medicines for improving the symptoms of dementia by means of the activation of cholinergic system have been developed. Further, on giving attention to the decrease of glutamatergic neurons and N-methyl-D-aspartic acid (hereinafter, abbreviated to “NMDA”) receptors, which is one of receptors of glutamic acid, a medicine to activate the NMDA receptor function has been also developed.
Recently, there are also some attempts to develop agonists for the peripheral-type benzodiazepine (hereinafter, optionally abbreviated to “BZω3”) receptors as the therapeutic agent for improvement in the symptoms of dementia. For example, it has been reported that N,N-di-n-hexyl-2-(4-fluorophenyl)indol-3-acetamide (hereinafter, abbreviated to “FGIN-1-27”) which is an agonist for BZω3 receptors, and some kinds of neurosteroids (for example, pregnenolone sulfate, allopregnanolone) have weak ameliorating effects in the animal models of learning impairment (active avoidance test, the radial-arm maze test, and water maze test) [Flood, J. F. et al., Brain Res., 448, 178-181 (1988); Flood, J. F. et al., Proc. Natl. Acad. Sci. U.S.A., 89, 1567-1571 (1992); Romeo, E. et al., J. Pharmacol. Exp. Ther., 270, 89-96 (1994)].
Until now, a lot of studies on the function of BZω3 receptors have been reported, and hence it has been shown that in the brain, BZω3 receptors often exist on the outer membrane of mitochondria in the glial cells and are involved in the uptake of cholesterol into the inner membrane of mitochondria, and then affect the biosynthesis of neurosteroids such as pregnenolone and consequently allopregnanolone and allotetrahydrodeoxycorticosterone. That is to say, it is considered that the stimulation onto the BZω3 receptor promotes the biosynthesis of neurosteroids in the brain, and these neurosteroids bind to the neurosteroid-recognition site (different site from the benzodiazepine receptor) in the complex of γ-aminobutyric acid A (hereinafter optionally abbreviated to “GABA-A”) receptor—benzodiazepine receptor—C1-ionchannel and affect the C1-channel opening process [Romeo, E. et al., J. Pharmacol. Exp. Ther., 262, 971-978 (1992)].
Since BZω3 receptor agonists modulate the function of GABA-A receptors via the biosynthesis of neurosteroids, it is suggested that the BZω3 receptor agonists could be possibly used as anxiolytics, antidepressants, hypnotics, antiepileptics, etc. For example, WO 99/28320 discloses that 2-aryl-8-oxodihydropurine derivatives of the formula (I), are selective and high-affinity BZω3 receptor agonists and are useful as medicines for treatment of, for example, anxiety-related disorders and depression.
In addition to the above, there are some other reports indicating that the BZω3 receptor agonists exhibit anxiolytic actions, but it is scarcely reported that said agonists exhibit an ameliorating effect on learning impairments, except for the above report as to FGIN-1-27.